FEP Medical Policy Manual Effective Date: April 15, 2018 Related Policies: 5.21.93 Rydapt (midostaurin) Genetic Testing for FLT3, NPM1, and CEBPA Variants in Description Treatment of acute myeloid leukemia (AML) is based on risk stratification, primarily related to patient age and tumor cytogenetics. In patients with cytogenetically normal AML, the identification of variants in several genes, including FLT3, NPM1, and CEBPA, has been proposed to allow for further segregation in the management of this heterogeneous disease. FDA REGULATORY STATUS Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Several laboratories offer these tests, including Quest Diagnostics, Medical Genetic Laboratories of Baylor College, Geneva Labs of Wisconsin, LabPMM, and ARUP Laboratories, are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test. In May 2017, the Food and Drug Administration granted approval for midostaurin (Rydapt, Novartis Pharmaceuticals). Rydapt is a targeted therapy to be used in combination with chemotherapy when an FLT3 variant is detected by the LeukoStrat CDx FLT3 Mutation Assay (Invivoscribe). FDA Premarket Approval was granted for the LeukoStrat CDx FLT3 Mutation Assay is a PCR-based, in vitro diagnostic test designed to detect internal tandem duplication (ITD) mutations and the tyrosine kinase domain mutations D835 and I836 in the FLT3 gene in genomic DNA extracted from mononuclear cells obtained from peripheral blood or bone marrow aspirates of patients diagnosed with acute myelogenous leukemia (AML). The LeukoStrat CDx FLT3 Mutation Assay is used as an aid in the selection of patients with AML for whom RYDAPT (midostaurin) treatment is being considered. The Leukostrat CDx FLT3 Mutation Assay is to be performed only at Laboratory for Personalized Molecular Medicine (LabPMM) LLC, a single site laboratory located at 6330 Nancy Ridge Dr., San Diego, CA 92121. (P160040) Original Policy Date: September 2014 Page: 1
Effective Policy Date: April 15, 2018 Page: 2 of 6 POLICY STATEMENT Genetic testing for FLT3 internal tandem duplication (FLT3-ITD), NPM1, and CEBPA variants may be considered medically necessary in cytogenetically normal acute myeloid leukemia (see Policy Guidelines section). Genetic testing for FLT3 internal tandem duplication, NPM1, and CEBPA variants is considered investigational in all other situations. Genetic testing for FLT3 tyrosine kinase domain variants is considered investigational. Genetic testing for FLT3, NPM1, and CEBPA variants to detect minimal residual disease is considered investigational. POLICY GUIDELINES Genetic testing for cytogenetically normal acute myeloid leukemia is intended to guide management decisions in patients who would receive treatment other than low-dose chemotherapy or best supportive care. The most recent World Health Organization classification (2016) reflects the increasing number of acute leukemias that can be categorized based on underlying cytogenetic abnormalities (ie, at the level of the chromosome including chromosomal translocations or deletions) or molecular genetic abnormalities (ie, at the level of the function of individual genes, including gene variants). These cytogenetic and molecular changes form distinct clinico-pathologic-genetic entities with diagnostic, prognostic, and therapeutic implications. 2 Conventional cytogenetic analysis (karyotyping) is considered to be a mandatory component in the diagnostic evaluation of a patient with suspected acute leukemia, because the cytogenetic profile of the tumor is considered to be the most powerful predictor of prognosis in AML and is used to guide the current risk-adapted treatment strategies. Molecular variants have been analyzed to subdivide AML with normal cytogenetics into prognostic subsets. In AML, three of the most frequent molecular changes with prognostic impact are variants of CEBPA, encoding a transcription factor, variants of the FLT3 gene, encoding a receptor of tyrosine kinase involved in hematopoiesis, and variant of the NPM1 gene, encoding a shuttle protein within the nucleolus. AML with mutated NPM1 or CEBPA were included as categories in the 2016 World Health Organization classification of acute leukemias. AML with FLT3 variants is not considered a distinct entity in the 2016 classification. The 2008 World Health Organization classification recommended determining the presence of FLT3 variants because of the prognostic significance. 3 Recent reviews (2012-2014) have highlighted the evolving classification of AML into distinct molecular subtypes. 4-7 GENETIC COUNSELING Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Effective Policy Date: April 15, 2018 Page: 3 of 6 BENEFIT APPLICATION Screening (other than the preventive services listed in the brochure) is not covered. Please see Section 6 General exclusions. Benefits are available for specialized diagnostic genetic testing when it is medically necessary to diagnose and/or manage a patient s existing medical condition. Benefits are not provided for genetic panels when some or all of the tests included in the panel are not covered, are experimental or investigational, or are not medically necessary. Experimental or investigational procedures, treatments, drugs, or devices are not covered (See General Exclusion Section of brochure). RATIONALE Summary of Evidence For individuals who have cytogenetically normal AML who receive genetic testing for variants in FLT3, NPM1, and CEBPA to risk-stratify AML, the evidence includes randomized controlled trials, retrospective observational studies, and systematic reviews of these studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and treatment-related mortality and morbidity. FLT3- ITD variants confer a poor prognosis, whereas NPM1 (without the FLT3-ITD variant) and biallelic CEBPA variants confer a favorable prognosis. The prognostic effect of FLT3 tyrosine kinase domain variants is uncertain. Data have suggested an overall survival benefit with transplantation for patients with FLT3-ITD, but do not clearly demonstrate an overall survival benefit of transplantation for patients with NPM1 and CEBPA variants. Major professional societies and practice guidelines have recommended testing for these variants to risk-stratify and to inform treatment management decisions, including possible hematopoietic cell transplant. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. SUPPLEMENTAL INFORMATION Practice Guidelines and Position Statements National Comprehensive Cancer Network Current National Comprehensive Cancer Network guidelines for acute myeloid leukemia (AML) (3.2017) provide the following recommendations 14 : For the evaluation for acute leukemia, bone marrow with cytogenetics (karyotype ± FISH [fluorescence in situ hybridization]) and molecular analyses (KIT, FLT3-ITD [internal tandem duplication], NPM1, CEBPA, and other mutations). Molecular abnormalities (KIT, FLT3-ITD, NPM1, CEBPA, and other mutations) are important for prognostication in a subset of patients (category 2A) and may guide therapeutic intervention (category 2B). These are useful for patients with normal karyotype (especially FLT3-ITD, NPM1 mutations) or core binding factor leukemia (especially KIT mutation). The guideline defined the following risk status based on molecular abnormalities: NPM1 without FLT3-ITD: favorable risk Isolated biallelic CEBPA: favorable risk FLT3-ITD: poor risk. European LeukemiaNet The 2010 European LeukemiaNet international expert panel recommendations for the diagnosis and management of adults with AML were updated in 2017. 39 The panel of 22 international experts on AML
Effective Policy Date: April 15, 2018 Page: 4 of 6 recommended that screening for NPM1, CEBPA, and FLT3 variants should be part of the diagnostic workup in patients with cytogenetically normal AML because they define disease categories that can inform treatment decisions. Table 1 outlines the risk stratification by genetic variants, and Table 2 summarizes recommended conventional care regimens based on risk category and age. Table 1 Risk Stratification by Genetic Variant Genetic Variant Biallelic CEBPA Mutated NPM1 without FLT3-ITD Mutated NPM1 with FLT3-ITD (low allelic ratio) Mutated NPM1 with FLT3-ITD (high allelic ratio) Wild-type NPM1 without FLT3-ITD Wild-type NPM1 with FLT3-ITD (low allelic ratio) Wild-type NPM1 with FLT3-ITD (high allelic ratio) Adapted from Dohner et al (2017). 39 ITD: internal tandem duplication. Risk Category Adverse Table 2 Conventional Care Regimens by Risk and Age Categories Risk and Age Categories Conventional Care Patients 18 to 60/65 years 2 to 4 cycles intermediate-dose cytarabine Allogeneic HCT from matched related or unrelated donor 2 to 4 cycles intermediate-dose cytarabine High-dose therapy and autologous HCT Adverse Allogeneic HCT from matched related or unrelated donor Patients >60/65 years 2 to 3 cycles intermediate-dose cytarabine /adverse Consider allogeneic HCT from matched related or unrelated donor Investigational therapy Adapted from Dohner et al (2017). 39 HCT: hematopoietic cell transplant. Not applicable. U.S. Preventive Services Task Force Recommendations Medicare National Coverage There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers. REFERENCES 1. American Cancer Society (ACS). What Are the Key Statistics About Acute Myeloid Leukemia? 2017; https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html. Accessed December 11, 2017. 2. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. May 19 2016;127(20):2391-2405. PMID 27069254 3. Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. Jan 21 2010;115(3):453-474. PMID 19880497 4. Liersch R, Muller-Tidow C, Berdel WE, et al. Prognostic factors for acute myeloid leukaemia in adults--biological significance and clinical use. Br J Haematol. Apr 2014;165(1):17-38. PMID 24484469 5. Khan I, Altman JK, Licht JD. New strategies in acute myeloid leukemia: redefining prognostic markers to guide therapy. Clin Cancer Res. Oct 1 2012;18(19):5163-5171. PMID 22893630
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Effective Policy Date: April 15, 2018 Page: 6 of 6 27. Ahn JS, Kim JY, Kim HJ, et al. Normal karyotype acute myeloid leukemia patients with CEBPA double mutation have a favorable prognosis but no survival benefit from allogeneic stem cell transplant. Ann Hematol. Jan 2016;95(2):301-310. PMID 26537612 28. Brunner AM, Li S, Fathi AT, et al. Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission. Br J Haematol. Nov 2016;175(3):496-504. PMID 27434660 29. Versluis J, In 't Hout FE, Devillier R, et al. Comparative value of post-remission treatment in cytogenetically normal AML subclassified by NPM1 and FLT3-ITD allelic ratio. Leukemia. Jan 2017;31(1):26-33. PMID 27416910 30. Bornhäuser M, Illmer T, Schaich M, et al. Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood. Mar 1 2007;109(5):2264-2265; author reply 2265. PMID 17312001 31. DeZern AE, Sung A, Kim S, et al. Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. Biol Blood Marrow Transplant. Sep 2011;17(9):1404-1409. PMID 21324374 32. Doubek M, Muzik J, Szotkowski T, et al. Is FLT3 internal tandem duplication significant indicator for allogeneic transplantation in acute myeloid leukemia? An analysis of patients from the Czech Acute Leukemia Clinical Register (ALERT). Neoplasma. Jan 2007;54(1):89-94. PMID 17233551 33. Gale RE, Hills R, Kottaridis PD, et al. No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. Blood. Nov 15 2005;106(10):3658-3665. PMID 16076872 34. Guieze R, Cornillet-Lefebvre P, Lioure B, et al. Role of autologous hematopoietic stem cell transplantation according to the NPM1/FLT3-ITD molecular status for cytogenetically normal AML patients: a GOELAMS study. Am J Hematol. Dec 2012;87(12):1052-1056. PMID 22911473 35. Laboure G, Dulucq S, Labopin M, et al. Potent graft-versus-leukemia effect after reduced-intensity allogeneic SCT for intermediate-risk AML with FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD. Biol Blood Marrow Transplant. Dec 2012;18(12):1845-1850. PMID 22766221 36. Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood. Dec 01 2006;108(12):3654-3661. PMID 16912228 37. Knapper S, Russell N, Gilkes A, et al. A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML. Blood. Mar 2 2017;129(9):1143-1154. PMID 27872058 38. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. Aug 3 2017;377(5):454-464. PMID 28644114 39. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. Jan 26 2017;129(4):424-447. PMID 27895058 POLICY HISTORY Date Action Description September 2014 New Policy September 2015 Update Policy Policy updated with literature review; references 10-13 and 20-22 added. Title revised and medically necessary statement added for CEBPA mutation. March 2018 Update Policy Policy updated with literature review through November 6, 2017; references 2, 16-20, 23-26, 28, and 36-38 added. Policy statements unchanged. Title changed to Genetic Testing for FLT3, NPM1, and CEBPA Variants in